Cyclooxygenase-2 Induced Pancreatic Cancer

环氧合酶 2 诱发胰腺癌

基本信息

  • 批准号:
    8212143
  • 负责人:
  • 金额:
    $ 31万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-04-01 至 2014-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Investigations into the role of cyclooxygenase-2 (COX-2) in pancreatitis and pancreatic cancer have been very limited. A recently generated transgenic mouse that over- expresses COX-2 under the control of a keratin 5 promoter, K5.COX-2, develops spontaneous pancreatitis leading to pancreatic adenocarcinoma that has many of the same histological and molecular characteristics as the human disease. This occurs with a 100% incidence and is fatal by 8 months of age. The major prostaglandin (PG) product, PGE2, binds to one or more of the 4 EP receptors. EP2 and EP4 are linked to adenylate cyclase causing an increase in cAMP and subsequent activation of protein kinase A (PKA) and phosphorylation of CREB. Preliminary data indicate that the cAMP/PKA/pCREB pathway is highly activated in pre-lesion pancreata of K5.COX-2 mice, however, the MAPK/Akt/NFkB pathway is also highly activated. We hypothesize that activation of both the cAMP/PKA/pCREB and MAPK/Akt/NFkB signaling pathways are required for a full neoplastic response as is the inflammatory response, and that inflammation is driving the metaplastic and neoplastic changes. Aim 1 will determine the requirement for PG signaling through the cAMP/PKA/pCREB pathway for adenocarcinoma development by generating transgenic mice with inducible, targeted activated CREB on a wildtype background, and dominant negative (dn)CREB on the K5.COX-2 background. Aim 2 will determine the critical involvement of MAPK/Akt/NFkB signaling in adenocarcinoma development through the use dnAkt/K5.COX-2 bitransgenic mice and the use of MAPK and NFkB inhibitors. Activation of c-Src, EGF receptors, Erk, Akt and NFkB will be assessed in wild type, pre-lesion and lesions from K5.COX-2 pancreata. Aim 3 will determine whether prostaglandins are driving acinar metaplasia by elevating cytokines that then recruit leukocytes. The effect of inhibition of COX-2 with celecoxib, or of inhibiting cytokine synthesis with pentoxyfylline, on cytokine expression, inflammatory cell infiltration and the development of acinar metaplasia and pancreatic cancer will be assessed. The effect of inhibition of COX-2 or cytokine synthesis on inflammatory cell infiltration in established lesions will also be determined to assess whether this will prevent further progression or reversion of the disease. PUBLIC HEALTH RELEVANCE: The proposed studies are significant because pancreatic cancer is one of the most fatal of all human malignancies and the lack of good animal models has severely hampered research into its etiology, prevention and treatment. Because of the associations between chronic inflammation, COX-2 and human pancreatic cancer, it is likely that the proposed work will generate information on the signaling pathways and receptors that are critical determinants in pancreatic cancer development, which should be useful for guiding future studies on chemoprevention and therapy.
描述(由申请人提供):环氧化酶-2 (COX-2)在胰腺炎和胰腺癌中的作用的研究非常有限。在角蛋白5启动子K5的控制下,最近产生的过表达COX-2的转基因小鼠。COX-2,发展为自发性胰腺炎,导致胰腺腺癌,具有许多与人类疾病相同的组织学和分子特征。该病的发病率为100%,到8个月大时可致死性。主要的前列腺素(PG)产物PGE2与4种EP受体中的一种或多种结合。EP2和EP4与腺苷酸环化酶相关,导致cAMP增加,随后激活蛋白激酶A (PKA)和CREB磷酸化。初步数据表明,cAMP/PKA/pCREB通路在K5病变前胰腺中高度激活。然而,COX-2小鼠的MAPK/Akt/NFkB通路也高度激活。我们假设cAMP/PKA/pCREB和MAPK/Akt/NFkB信号通路的激活是完全肿瘤反应和炎症反应所必需的,并且炎症正在驱动化生和肿瘤变化。Aim 1将通过在野生型背景下培养具有可诱导的靶向激活CREB的转基因小鼠,以及在K5上具有显性阴性(dn)CREB的转基因小鼠,来确定通过cAMP/PKA/pCREB途径的PG信号通路在腺癌发展中的需求。cox - 2的背景。目的2将通过使用dnAkt/K5来确定MAPK/Akt/NFkB信号在腺癌发展中的关键作用。COX-2双转基因小鼠及MAPK和NFkB抑制剂的使用。c-Src、EGF受体、Erk、Akt和NFkB的激活将在野生型、病变前和K5病变中进行评估。cox - 2 pancreata。目的3将确定前列腺素是否通过提高细胞因子进而募集白细胞来驱动腺泡化生。将评估塞来昔布抑制COX-2或己氧基茶碱抑制细胞因子合成对细胞因子表达、炎症细胞浸润以及腺泡化生和胰腺癌发展的影响。抑制COX-2或细胞因子合成对已建立病变的炎症细胞浸润的影响也将被确定,以评估这是否会阻止疾病的进一步进展或逆转。公共卫生相关性:拟议的研究意义重大,因为胰腺癌是所有人类恶性肿瘤中最致命的一种,缺乏良好的动物模型严重阻碍了对其病因、预防和治疗的研究。由于慢性炎症、COX-2与人类胰腺癌之间存在关联,因此本研究可能会获得胰腺癌发展关键决定因素信号通路和受体的信息,这将有助于指导未来的化学预防和治疗研究。

项目成果

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SUSAN M FISCHER其他文献

SUSAN M FISCHER的其他文献

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{{ truncateString('SUSAN M FISCHER', 18)}}的其他基金

Obesity and Pancreatic Cancer: The Role of IGF-1
肥胖和胰腺癌:IGF-1 的作用
  • 批准号:
    8193238
  • 财政年份:
    2009
  • 资助金额:
    $ 31万
  • 项目类别:
Obesity and Pancreatic Cancer: The Role of IGF-1
肥胖和胰腺癌:IGF-1 的作用
  • 批准号:
    7653538
  • 财政年份:
    2009
  • 资助金额:
    $ 31万
  • 项目类别:
Obesity and Pancreatic Cancer: The Role of IGF-1
肥胖和胰腺癌:IGF-1 的作用
  • 批准号:
    8259466
  • 财政年份:
    2009
  • 资助金额:
    $ 31万
  • 项目类别:
Cyclooxygenase-2 Induced Pancreatic Cancer
环氧合酶 2 诱发胰腺癌
  • 批准号:
    8029551
  • 财政年份:
    2008
  • 资助金额:
    $ 31万
  • 项目类别:
Cyclooxygenase-2 Induced Pancreatic Cancer
环氧合酶 2 诱发胰腺癌
  • 批准号:
    7463485
  • 财政年份:
    2008
  • 资助金额:
    $ 31万
  • 项目类别:
Cyclooxygenase-2 Induced Pancreatic Cancer
环氧合酶 2 诱发胰腺癌
  • 批准号:
    7758221
  • 财政年份:
    2008
  • 资助金额:
    $ 31万
  • 项目类别:
Cyclooxygenase-2 Induced Pancreatic Cancer
环氧合酶 2 诱发胰腺癌
  • 批准号:
    7589786
  • 财政年份:
    2008
  • 资助金额:
    $ 31万
  • 项目类别:
COX-2 Driven Pancreatic Adenocarcinoma
COX-2驱动的胰腺腺癌
  • 批准号:
    7126617
  • 财政年份:
    2006
  • 资助金额:
    $ 31万
  • 项目类别:
COX-2 Driven Pancreatic Adenocarcinoma
COX-2驱动的胰腺腺癌
  • 批准号:
    7268125
  • 财政年份:
    2006
  • 资助金额:
    $ 31万
  • 项目类别:
VII International Skin Carcinogenesis Conference (ISCC)
第七届国际皮肤癌会议(ISCC)
  • 批准号:
    7224758
  • 财政年份:
    2006
  • 资助金额:
    $ 31万
  • 项目类别:

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